A fast growing body of evidence suggests that poly(ADP-ribose) polymerase (PARP) activation plays an important role in ischemic brain damage. However, the mechanisms underlying PARP neurotoxicity remain unstudied. Based on the evidence suggesting the possible effects of a PARP-produced NAD+ decrease on mitochondria permeability transition (MPT) and oxidative stress, experiments are designed in this proposal to test the hypothesis that PARP stimulation elicits neuronal death by potentiating MPT and oxidative damage. Primary murine neuronal mono- cultures are used as in vitro models. Both PARP inhibitors and PARP gene disruption are used to depress PARP activation. This study may suggest novel mechanisms of excitotoxic and oxidative neuronal death, and provide new insights for attenuating ischemic brain damage.